Retrosteroid a ring formation

ABSTRACT

A PROCESS FOR PRODUCING KNOWN RETROSTEROIDS OF THE FORMULA:   1-R1,2-R2,3-(O=),4-R4,6-R6,7-R7,11-R11,16-R16-ANDROST-4-   ENE WHERE C17 IS Z   WHEREIN: R1 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKOXY, AND LOWER ALKYLTHIO; R2 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKOXY, AND LOWER ALKYLTHIO; R6 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKYLTHIO, LOWER AKLANOYLTHIO, AND HALO; R7 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKYLTHIO, LOWER ALKANOYLTHIO, AND HALO; R11 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HYDROXY AND LOWER ALKANOYLOXY; R16 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, HYDROXY, LOWER ALKOXY, LOWER ALKANOYLOXY, AND, WHEN THE 17B-SUBSTITUENT IS ACETYL OR SUBSTITUTED ACETYL, FLUORINE; Z IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF CARBONYL, (17B-HYDROXY-17-A-LOWER ALKANOIC ACID LACTONE), AND   &gt;C(-R17ALPHA)-R17BETA   R17B IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROXY, LOWER ALKANOYLOXY, AND   Y-CH2-CO-   Y IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALO, AND HYDROXY; R17A, WHEN R17B IS HYDROXY AND LOWER ALKANOYLOXY, IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALIPHATIC HYDROCARBYL, AND WHEN R17B IS   Y-CH2-CO-   IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN ALKYL, HYDROXY, LOWER ALKANOYLOXY, AND HALO; Q WHEN TAKEN ALONE, IS OXO; T1 WHEN TAKEN ALONE, IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL OXY AND LOWER ALKOXY; AND T1 AND Q, WHEN TAKEN TOGETHER ARE NITROLO.

3,766,213 RETROSTEROID A-RING FORMATION Andor Furst, Basel, and Wolfgang Koch, Riehen, Switzerland, and Milan Radoje Uskokovic, Upper Montclair, N.J., assignors to Hotfmann-La Roche, Inc., Nutley, NJ.

No Drawing. Original application Apr. 19, 1966, Ser. No. 543,526, now Patent No. 3,591,607. Divided and this application Jan. 6, 1971, Ser. No. 104,470

Int. Cl. C07d 7/26 U.S. Cl. 260-343.2 S Claims ABSTRACT OF THE DISCLOSURE A process for producing known retrosteroids of the formula:

wherein R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, and halo;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, and halo;

R is a member selected from the group consisting of hydrogen, hydroxy and lower alkanoyloxy;

R is a member selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoXy, lower alkanoyloxy, and, when the l7B-substituent is acetyl or substituted acetyl, fluorine;

Z is a member selected from the group consisting of carbonyl, (17l3-hydroxy-17a-lower alkanoic acid lactone), and

m i a member selected from the group consisting of hydroxy, lower alkanoyloxy, and

Y is a member selected from the group consisting of hydrogen, halo, and hydroxy;

R when R is hydroxy and lower alkanoyloxy, is a member selected from the group consisting of hydrogen and lower aliphatic hydrocarbyl, and when R17 is o YCHz is a member selected from the group consisting of hydrogen alkyl, hydroxy, lower alkanoyloxy, and halo; Q when taken alone, is oxo; T when taken alone, is a member selected from the group consisting of alkali metal oxy and lower alkoxy; and T and Q, when taken together are nitrolo.

United States Patent 0 3,766,213 Patented Oct. 16, 1973 CROSS-REFERENCE TO RELATED APPLICATION This application is a division of U.S. patent application Ser. No. 543,526, filed Apr. 19, 1966, now U.S. Pat. No. 3,591,607.

DETAILED DESCRIPTION OF THE INVENTION This invention is concerned with the synthesis of retro steroids and more particularly with a method for the formation of the A-ring of retrosteroids.

Recently, it was discovered that l0a-methyl-9p-steroids, or retrosteroids, have pharmacological activity which diifers from that of the corresponding normal steroid; and, in general, retrosteroids have been found to produce certain desired pharmacological activities with substantially reduced or no side effects when compared with normal steroids.

In the past retrosteroids have been synthesized in low yields from normal steroids via irradiation. This treatment effects isomerization of the normal steroid nucleus to the 9B,10a-configuration, thereby forming a retrosteroid which can be employed as a pharmaceutical as such or converted by known techniques to other pharmacologically-active retrosteroids.

It is an object of this invention to provide a practical route and novel intermediates for the manufacture of retrosteroids having the general formula:

wherein R is hydrogen, lower alkyl, lower alkoxy, or lower alkylthio; R is hydrogen, lower alkyl, lower alkoxy, or lower alkylthio; R is hydrogen or lower hydrocarbyl free from aliphatic, i.e., olefinic or acetylenic, unsaturation, e.g., lower alkyl or phenyl; R is hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, or halo; R is hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, or halo; R is hydrogen, hydroxy, or lower alkanoyloxy; R is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, or, when the l7fi-substituent is acetyl or substituted acetyl, can also be fluorine; Z is carbonyl, (17fi-hydroxy-17alower alkanoic acid lactone), or

ina

R is hydroxy, lower alkanoyloxy, or

is hydroxy or lower alkanoyloxy, is hydrogen or lower aliphatic hydrocarbyl, and, when R is O YCH: ii-

is hydrogen, alkyl, hydroxy, lower alkanoyloxy, or halo.

The compounds of Formula I may be further illustrated by subgeneric formulae:

wherein R R R R R R and Y are as previously defined; A is carbonyl, (l7fl-hydroxy-17u-lower alkanoic acid lactone), or

/ORI

R is hydrogen or lower alkanoyl; R is hydrogen or lower aliphatic hydrocarbyl; R is hydrogen, lower alkyl, hydroxy, lower alkoxy, or lower alkanoyloxy; R is hydrogen, lower alkyl, hydroxy, lower alkanoyloxy, or fiuoro; and R is hydrogen, lower alkyl, hydroxy, lower alkoxy, or halo.

Especially preferred products of the process of this invention are the 9 9,l0a-androst-4-en-3-ones of the formula:

(Ib-l) wherein n is an integer having a value of from 0 to 6,

x is an integer having a value of 2n-]-l, 2n-1 or 2n--3 and y is an integer having a value of from 0 to 1.

As used herein, the term lower, as applied to aliphatic hydrocarbyl groups, comprehends both straight and branched chain saturated and unsaturated hydrocarbon groups of up to about 6 carbons, including lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and the like; and lower alkynyl groups such as vinyl, and the like; and lower alkynyl groups such as ethinyl, and the like. Similarly, the term lower alkanoyl" comprehends groups such as acetyl, and the like; and the term lower alkanoyloxy" comprehends groups such as acetoxy, and the like. The term halogen comprehends all four halogens, i.e., iodine, bromine, chlorine, and fluorine.

Illustrative of the products of the process of this invention are 17fl-hydroxy-9fi, l0a-androst-4-en-3-one, 17B-hydroxy-17a-methyl-9fi,l0a-androst-4-en-3-one, 17/3-hydroxy-l7u-ethyl-9fi, l0a-androst-4-en-3-one, 1713-hydroxy-l7u-hexyl-9/3, 1 0a-androst-4-en-3-one, I7B-hydroxy-l7a-vinyl-9p,l0a-androst-4-en-3-one, 17 8-hydroxy-l7a-hexenyl-9fi,l0a-androst-4-en-3-one, 17a-ethinyl-17fi-hydroxy-9i3,10a-androst-4-en-3-one, 17fl-hydroxy-17a-hexinyl-9p,10a-androst-4-en-3-one,

as well as their acetyl or benzoyl esters,

9,8,10a-androst-4-ene-3, l7-dione, 9,8,l0a-androst-4-en-3-one l7fi-hydroxy-17a-acetic acid lactone, 9 3,10a-pregn-4-ene-3,20-dione, l7a-hydroxy-9 8,10a-pregn-4-ene-3,2-0-dione, 17a-methyl-9/8,10a-pregn-4-ene-3,20-dione, 17a-ethyl-9fi,l0a-pregn-4-ene-3,20-dione, l7a-hexyl-9p,lOwpregn-4-ene-3,ZO-dione, 21-hydroxy-9p, l0a-pregn-4-ene-3,20-dione,

and the like.

The process of this invention employs a known sequence of reactions for the synthesis of the steroidal A-ring which broadly comprises (1) carboxyethylation of a tricyclic compound, (2) cyclization of the carboxyethyl compound to form an enol lactone, (3) conversion of the enol lactone to an aldol, and (4) rearrangement and dehydration of the aldol to complete the formation of the steroid A-ring. It has been found by this invention that this sequence of reactions, when applied to certain tricyclic compounds, as hereinafter defind, provides a completely stereospecific synthesis of retrosteroids. The process of this invention is broadly illustrated by the following general reaction scheme:

carboxyethylation H0,

The tricyclic starting materials employed in the process of this invention are broadly illustrated by the formula:

R (II) Subgeneric to these compounds are the desA-9/8,10;8-androstanes of the formula:

(IIa) (IIb) wherein R R R R R, R R A, Z, and Y are as previously defined.

As will be appreciated, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of substitutents of the starting materials. However, in order to obtain unnatural 95,100;- steroids of Formula I, it is necessary or desirable to protect certain of the substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steriod of Formula I possessing the unnatural 9;8,10a-configuration is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaciton step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substitutents which are susceptible to being protected are exemplified by the 16-hydroxy group, the 17/3-hydroxy group, the l7a-hydroxy or 20-oxo group, the Zl-hydroxy group, or the 17-oxo group of a compound of Formula II.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, to yield a 17-lower alkylenedioxy or 20-lower alkylenedioxy compound, i.e., a 17-ketal or a 20-ketal.

The 16-hydroxy, 17ot-hydroxy, l7 8-hydroxy or 21-hydroxy moieties can be protected by esterification and/or etherification of the hydroxy group. Any available acid which will form an ester .that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable.

Exemplary acids useful for this purpose are lower alkanoic acids, e.g., acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkyldicarboxylic acids, e.g., succinic acid. Also, protection for the IGzx-hYdIOXY, 17a-hydroxy, or 2l-hydroxy substituent can be efiected by forming the lower alkyl ortho esters. Suitable ether protecting groups i.e., for example, the tetrahydropyranyl ether, the benzhydryl ether, the allyl ether, the benzyl ether, the trityl ether, the methoxymethyl ether, the tert.-butyl ether or lower alkyl ethers, such as the methyl ether.

In compounds containing the dihydroxyacetone side chain at C-17 (for example, compounds of Formula I wherein R is hydroxy), the side chain at 0-17 can be protected by forming the 17,20;20,2l-bis-rnethylenedioxy group or by forming a 17,2l-acetal or ketal group, or by forming a 17,21-diester. The 17,21-acetal or ketal and 17,21-diester hinder the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,20;20,21-bis-methylenedioxy derivatives actually convert the ketone to a nonreactive derivative. When both a l6ot-hydroxy and 17mhydroxy substituent are present, these groups can be protected via formation of a 16a,l7 x-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 17cchydroxy nor 2l-hydroxy substituent but there is present a 20-oxo group, the 20oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the 17-acetyl side chain can be protected via conversion to a l7-(a-hydroxyethyl)-side chain. Regeneration of the 17-acetal side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic sol vent such as glacial acetic acid. Similarly, in compounds contaning a l7-oxo group, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the 17-oxo group can be reduced to a 17,?- OH, 17u-H moiety, from which, when desired, the 17- oxo moiety can be regenerated by oxidation, as described above. Furthermore, a 20-hydroxy or 17,8-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoie acid such as acetic acid, caproic acid, or the like.

The :,17uor l7a,2l-acetals and ketals above discussed can be formed by reacting 1611,17 a-bis-hydroxy or l7ot,2l-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e., a lower alkyleneglycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethyl-ketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone, and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcanboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketones; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone, and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxyphenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromaticlower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and

heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1,1,1-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g., p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxybenzaldehydes (e.g., o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g., veratraldehyde), hydroxybenzaldehydes (e.g., salicylaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehyde and pethylbenzaldehyde), di(lower alkyl)-benzaldehydes (e.g., o,p-dimethylbenzaldehyde); monocyclic carboxylic aro matic lower alkanals, such as phenylacetaldehyde, aphenylpropionaldehyde, B phenylpropionaldehyde, 4- phenylbutyraldehyde, aromatically substituted halo, lower alkoxy; hydroxy, and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,ot,a trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g., p-chloroacetophenone and pchloropropiophenone); (lower alkoxy)-phenyl lower alkyl ketones (e.g., p-anisyl methyl ketone); di-(lower alkoxy)-pheny1 lower alkyl ketones; hydroxy-phenyl lower alkyl ketones (lower alkyl)-phenyl lower alkyl ketones (e.g., methyl p-tolyl ketone); di-(lower alkyl)- phenyl lower alkyl ketones (o,p-xylyl methyl ketone); benzophenone, and monoor bis-substituted halo, lower alkoxy, hydroxy, and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl-3-butanone and l-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the l6oc,17ot or 17u,2l-bis-hydroxy grouping form an acetal or ketal group of the formula:

wherein P is individually selected from the group consisting of hydrogen and lower alkyl; W is individually selected from the group consisting of lower alkyl and aryl; and P and W taken together are lower alkylene. The term lower alkylene comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned; but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

The tricyclic starting materials of Formula II form no part of the presently claimed invention. Nevertheless, for convenience, methods for their synthesis are set forth below.

The desA-S-one tricyclic compounds of Formula II are generally produced either (a) by the hydrogenation of a desA-9-en-5-one having the formula:

CH3 n 1. H J CH3 wherein R R R R and Z are as previously defined to produce a product having a saturated 17u-substituent or (b) by the hydrogenation of a l7-oxo-desA-9-en-5-one of Formula III followed by a Grignard reaction with an unsaturated hydrocarbyl Grignard reagent to provide an unsaturated 17a-substituent.

The hydrogenation, besides inserting a hydrogen atom in each of the 9- and -positions, can also simultaneously elfect hydrogenation of other groups in the molecule. For example, a C-20-keto group can be hydrogenated to the corresponding carbinol or a C-l7-lower alkenyl group or a C-17-lower alkynyl group can be hydrogenated to the corresponding C-17-lower alkyl group. Compounds of Formula II having a Not-unsaturated hydrocarbon substituent can be prepared from 913,l0a-desA-l7-oxo-androstan-S-one via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for example, by forming, S-ketals without concurrent blocking of the 17-keto group.

The hydrogenation of the desA-androst-9-en-5-ones and the desA-pregn-9-en-5-ones is elfected by catalytic hydrogenation, suitably using a precious metal catalyst. Especially preferred precious metal catalysts are palladium, platinum, and rhodium. It is particularly advantageous to use rhodium, for example, rhodium on charcoal or rhodium on alumina. This catalytic hydrogenation is suitably eifected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, or the like, or a mineral acid, for example, a hydrohalide acid, such as hydrochloric acid, or the like. The reaction can be conducted at, above or below room temperature, for example, from about 5 C. to about C. However, it is preferably conducted at a temperature between about 0 C. and about 35 C.

The desA-androst-9-en-5-ones or desA-l7B-pregn-9-en- S-ones of Formula III can be prepared from natural steroids by a variety of methods. For example, the desA- androst-9-en-5-ones or desA-17,3-pregn-9-en-5-ones can be prepared from natural steroids of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn-4-ene series by a reaction sequence which involves as a first step an oxidative ring opening of ring A of the natural steroid. For this method there can be used as starting materials natural steroids of the 3-oxo-androst-4-ene or 3-oxo-l7 3-pregn-4-ene series of th formula:

where in R, R", R R and Z are as previously defined.

When R is hydrogen, the oxidative ring opening of a natural steroid of Formula IV yields a 5-oxo-3,5-seco-A- norandrostan-B-oic acid or a 5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula:

(IVa) wherein R, R", R and Z are as previously defined.

When R is low alkanoyloxy, the oxidative ring opening of a natural steroid of Formula IV yields a 5-oxo-3,5-

H CHs (IVb) wherein R R", R, and Z are as previously defined.

When R is lower alkanoyloxy, the oxidative ring opening of a natural steroid of Formula IV yields a S-oxo- 3,5-seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A- norpregnan-3-oic acid of the formula:

C lower alkanoyloxy 1 wherein R R R and Z have the same meaning as above.

The oxidative ring opening of the compounds of Formula IV can be performed by a variety of methods. In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the oxonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about -80 C. and about 25 C. The resulting ozonides can be decomposed by conventional means, for example, by treatment with water, hydrogen peroxide in water, acetic acid, or ethyl acetate, or the like. The oxidative ring opening of a compound of Formula IV to a compound of Formulae IVa, IVb, or We can also be effected by other oxidation means, for example, by treatment with hydrogen peroxide. It should be noted that an oxidative ring opening by either ozonolysis or by treatment with hydrogen peroxide does not require protection of any of the substituents at C-16 or C-17. However, as stated above, it may be desirable to protect these substituents against some subsequest reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment with sodium periodate and potassium permanganate in potassium carbonate solution; and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16-, 175-, or 21- hydroxy group, preferably, for the purpose of this reaction, with nonaromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained 5-oxo-3,S-seco-A-norandrostan-3-oic acid or S-oxo-3,S-seco-A-norpregnan-3-oic acid or Formula IVa may be converted into a mixture of a 10a-desA-androstan- 5-one and a IOfi-desA-androstan-S-one or a mixture of a IOa-desA-pregnan-S-one and a IOfi-desA-pregnan-S-one as illustrated by the formula:

wherein R, R", R and Z have the same meaning as above.

The conversion of a compound of Formula IVa into the compounds of Formula IVd is elfected by pyrolysis. Prior to' effecting the pyrolysis, it is desirable to convert the 3-0ic acid of Formula IVa into a corresponding metal salt, for example, an alkali metal salt such as the sodium salt. The pyrolysis can be conducted at atmospheric pressure or in a vacuum, but it is preferably conducted in a vacuum, at a temperature of from about 200 C. to about 350 C. in the presence of a proton acceptor, e.g., an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl acetate, sodium bicarbonate, or the like. Especially preferred is a vacuum of from about 0.001 to about 0.5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e., at a pH greater than 7.

It should be noted that though the pyrolysis of a compound of Formula IVa yields both IOB-compounds and IOa-compounds, and though either of these isomers can be used in the subsequent halogenation and dehydrohalogenation steps of this reaction sequence, it is sometimes preferable to convert the IOB-compound of Formula IVd into the corresponding l0acompound. his conversion can be effected by treating a l0fi-desA-androstan-5-one or desA-pregnan-S-one of Formula IVd with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of Formula IVa to compounds of Formula IVd can be effected without protection of any of the substituents which might be present at C-16 or C-17. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of Formula IVa to compounds of Formula IVd can be effected with protecting groups present on substituents in the C-16 or 0-17 position.

Compounds of Formula IVd can also be formed from a compound of Formula IVa via the formation of an enollactone of a compound of Formula IVe, i.e., via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxo-pregn- 5-ene-3-one of the formula:

(IVe) wherein R R", R, and Z have the same meaning as above, which can then be reacted with a Grignard reagent,

1 1 such as phenyl magnesium bromide or phenyl lithium, to form the resulting aldol of, for example, the formula:

(lvt wherein R R", R and Z have the same meaning as above, which, upon treatment with an alkali metal hydroxide, such as potassium hydroxide, at an elevated temperature, for example, from about 200 C. to about 240 C., is converted to the corresponding 10m-desA-androstan- S-one or 10a-desA-pregnan-5-one of Formula IVd.

The lactones of Formula IVb can be treated with an alkali metal hydroxide such as sodium hydroxide to give the salt of the same keto acid. Without isolation, this salt can then be subjected to pyrolysis yielding a mixture of an 1l-hydroxy-IOa-desA-androstan-S-One and an ll-hydroxy-10,8-desA-androstan--one or a mixture of an 11- hydroxy-l0a-desA-pregnan-5-one and an ll-hydroxy-lOfldesA-pregnan-S-one, as illustrated by the formula:

This pyrolysis of the alkali metal salt derived from a compound of Formula IVb can be effected under the same conditions as described above for the pyrolysis of a compound of Formula IVa to compounds of Formula IVd. Both the IOB-compounds and the wot-compounds of Formula IVg can be subjected to the subsequent steps of this reaction sequence.

As the next step in this sequence, the compounds of Formula IVg may be esterified with an organic carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, and the like, to provide an ester of the formula:

(IVh) wherein R, R R and Z are as previously defined and E represents the acid residue.

1V1) wherein R R R R and Z have the same meaning as above, and Hal is a halogen atom (preferably Br or Cl).

Dehydrohalogenation of a compound of Formula IVi then yields a desired starting material of Formula III. Keto groups, except for the 5-keto group, may required protection prior to the halogenation. In the case of compounds containing the C-17 dihydroxyacetone side chain, wherein R is hydroxy, this protection can be effected by formation of the 17a,20;20,2l-bis-methylenedioxy derivative. In other cases wherein a 0-17 0x0 or C-20 oxo group is present, protection can be effected by reduction to the corresponding carbinol either directly prior to the halogenationv step or prior to some other step in the reaction sequence leading to the compounds of Formulae IVd or IVh.

The halogenation can be effected with halogenating agents such as bromine, sulfuryl chloride, or the like. Bromination is especially preferred. The bromination is suitably effected by treatment with bromine at room temperature or below, preferably at ice temperature or below. Suitably it is conducted in an organic medium; for example, an organic acid such as acetic acid; an ether such as an anhydrous either, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst.

The subsequent dehydrohalogenation of a compound of Formula IVi is preferably conducted under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate (e.g., lithium carbonate) or an alkali metal halogenide (e.g., a lithium halide) in an anganic solvent such as a di(lower alkyl)-foramide, or with an organic base such as colloidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50 C. to about 150 C., preferably from about C. to about C.

Separation of the desired product desA-androst-9-en-5- one or desA-pregn-9-en-5-one can be effected by conventional means. The halogenation procedure may result in halogenated by-products in addition to the desired intermediate of Formula IVi. Acordingly, the separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the halogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional means, for example, by column chromatography, to yield the desired compound. An exemplary dehalogenation means is treatment with zinc and sodium acetate in an acetic acid solution at an elevated temperature, for example, about 80 C.

In the case of compounds which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such a halogen atom against dehalogenation prior to subjecting the compound to the two-step sequence of halogenation and dehydrohalogenation of this embodiment. This protection can be effected, for example, by ketalization of the keto group.

As an alternative route to compounds of Formula III, the ll-hydroxy compound of Formula IVg can be subjected to esterification to convert the ll-hydroxy group to a leaving group in the ll-position. This esterification can be effected with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive derivative is meant, for example, a halide, e.g., a chloride, an anhydride, or the like. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the C-l6, C-17, or -21 position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the ll-position, are inorganic acids such as phosphoric acid; organic carboxylic acids such as anthraquinone fi-carboxylic acid; or organic sulfonic acids, for example, toluenesulfonic acids, especially p-toluenesulfonic acid; lower alkylsulfonic acids such as methanesulfonic acid and nitrophenylsulfonic acids, especially p-nitrophenylsulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. The above-described esterification of the ll-hydroxy compounds of Formula IVg yields compounds of the formula:

The leaving group can then be eliminated from the ll-position of a compound of Formula IVj resulting in a direct formation of a desA-androst-9-en-5-one or a desA-pregn-9-en-5-one of Formula III. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e., at a temperature between about room tem perature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula IVj with either an inorganic or organic base results in the formation of the desired compound of Formula III. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g., a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as di-lower alkylformamides, e.g., dimethylformamide; lower alkanoic acids, e.g., acetic acid; or the like. When a proton-accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e., if the solvent is basic, then the elimination can be conducted without the addition of a separate basicmaterial.

An alternative route to the tricyclic materials from an 11-hydroxy steroid of Formula IV comprises first converting the ll-hydroxy group to a leaving group by esterification, as described above, thereby forming a compound of the formula:

(IVk) 14 wherein R R R and Z have the same meaning as above, and LO represents the leaving group.

(IVm) wherein R R", R Z, and LO have the same meaning as above.

The oxidative ring opening of the A-ring can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of Formula IV. Pyrolysis of the so-formed compound of Formula IVm under the conditions described above for the pyrolysis of a compound of Formula IVa directly yields the desired desA-androst-9-en-5-one or desA-pregn-9-en-5-one of Formula HI. Th'us, pyrolysis of a compound of Formula IVm directly results in elimination of the leaving group in the ll-position as well as a splitting off of the residue of ring A attached to the 10-position. This procedure of starting from an ll-hydroxy steroid (preferably llu-hydroxy) of Formula IV and proceeding through intermediates of Formulae IVk and IVm to compounds of Formula III represents a particularly elegant procedure for preparing the latter compounds.

Compounds of Formula IVd also can be prepared from compounds of the formula:

R CH;

wherein R R R R and Z have the same meaning as above,

wherein R R R and Z have the same meaning as above.

A compound of Formula Va can then be converted to a compound of Formula IVd by removal of the residue of the A-ring, i.e., decarboxylation, by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g., ethanol, dioxane, ether, or the like. The decarboxylation yields mainly a 10a-isomer of Formula IVd but also a minor yield of the corresponding IOB-isomer.

Compounds of Formula V, wherein R is a hydroxy group, can be esterified to form compounds of the formula:

wherein R, R", R Z and LO have the same meaning as above.

The compounds of Formula Vb can be prepared from corresponding ll-hydroxy compounds by esterification as described above for the preparation of compounds of Formula IVj from compounds of Formula IVg. The compounds of Formula IVd can be prepared from compounds of Formula Vb in the same manner that compounds of Formula IVd are prepared from compounds of Formula Va, i.e., by oxidative ring opening of the A-ring of a compound of Formula Vb followed by elimination of the residue of the A-ring to yield a compound of Formula IVd. The oxidative ring opening of the compounds of Formula Vb can be performed by ozonolysis, which yields a compound of the formula:

on, LO RM R R (VI) wherein R and R are as previously defined; Q, when taken alone, is oxo; T, when taken alone, is hydroxy, alkali metal oxy, or lower alkoxy; Q and T, when taken together are nitrilo N); R when taken alone, is hydrogen or hydroxy, and is hydroxy only when --CQT is carboxy; T and R when taken together, are oxy; and R and R when R is hydrogen, form a carboncarbon bond, or, when R is hydroxy, or R and T together are 0x0, are both hydrogen.

Thus, the compounds represented by Formula VI include, n p-unsaturated nitriles:

CHR =CR CN (VIa) c p-unsaturated acids, their lower alkyl esters, or alkali metal salts:

CHR =CR --CO H (VIb) CHR =CR C( lower alkyl (VIc) CH'R =OR CO -alkali metal (VId) B-hydroxy acids;

HOCHR CHR CO H (VIe) and fi-lactones:

CHRLCHRZ :0 (vii) Illustrative examples of suitable compounds of Formula VII include nitriles such as acrylonitrile, methacrylonitrile, ethacrylonitrile, crotononitrile, a-methoxyacrylonitrile, B-methoxyacrylonitrile, a-methylthioacrylonitrile, fl-methylthioacrylonitrile, and the like; acids such as acrylic acid, methacrylic acid, ethacrylic acid, crotonic acid, a-methoxyacrylic acid, u-methylthioacrylic acid, and the like; as well as the lower alkyl, for example, methyl or ethyl, esters; or alkali metal, for example, sodium or potassium, salts of these acids; ,B-hydroxy acids such as ,B-hydroxypropionic acid, fi-hydroxybutyric acid, and the like; and ,B-lactones such as fl-propiolactone, fl-butylolactone, a-meth'yl-B-propiolactone, a-methoxy-fl-propiolactone, a-methylthio-fl-propiolactone, and the like.

Base catalysts which can be employed in this step include organic bases, including quaternary ammonium hydroxides such as benzyltrimethylammonium hydroxide, and the like, and alkali metal alkoxides such as sodium methoxide, potassium tert.-butoxide, and the like; and inorganic bases such as alkali metal hydroxides or hydrides, for example, sodium hydroxide, potassium hydroxide, or sodium hydride.

The temperature of the base-catalyzed reaction is not critical and temperatures of from between 0 C. and lower to 200 C. and higher are suitable, with temperatures of from about 0 to C. being preferred. It is preferred that the reaction be conducted in the presence of an inert organic solvent, i.e., a solvent which will not react with either the compound of Formula II or Formula VI. For example, when acrylonitrile is employed as the compound of Formula VI, acetonitrile or ketones cannot be employed as solvents. Preferred solvents include benzene, ether, dioxane, or lower alkanols, such as methanol, ethanol, and the like.

In this reaction, when R of the compound of Formula II is hydrogen, it is preferred that the 6-position be protected, for example, by condensation of the tricyclic compound of Formula II with ethyl formate to form a hydroxymethylene ketone and then condensation with methyl aniline to form a methylanilinomethylene ketone or with a thiol, such as an alkyl mercaptan, e.g. n-butyl mercaptan, an aralkyl mercaptan, e.g. benzyl mercaptan, an aryl mercaptan, e.g. thiophenol, to form an S-substituted thiomethylene ketone. These protecting groups are readily removed by basic hydrolysis. Absent such protecting groups, the compound of Formula II may be attacked in the 6-position.

The products of the base-catalyzed reaction are novel compounds which are represented by the formula:

(VII) wherein R R R R", R R Q, and Z are as previously defined; T when taken alone, is alkali metal oxy or lower alkoxy; and T and Q, when taken together, are nitrolo.

Thus, the immediate products of the reaction are nitriles, or salts or esters of carboxylic acids, which must 19 5,20-dioxo-2-methyl-3,5-seco-A-nor-9 3, 10a-pregnan-3- oil acid, 5,20-dioxo-6-methyl-3,5-seco-A-nor-9fi,10a-pregnan-3- oic acid, 5,20-dioxo-7-methy13,5-seco-A-nor-9B-10a-pregnan-3- oic acid, 5,20-dioxo-11-hydroxy-3 ,5-seco-A-nor-9fl, IOa-pregnan- 3-oic acid, 5,20-dioxo-16-methyl-3,5-seco-A-nor-9 3,10a-pregnan- 3-oic acid, 5,20-dioxo-16-hydroxy-3,5-seco-A-nor-9p,lOa-pregnan- 3-oic acid, 5,20-dioxo-16-methoxy-3,5-seco-A-nor-9fl,wot-pregnan- 3oic acid,

as well as the alkali metal salts and lower alkyl esters of the foregoing acids.

The second step of the process of this invention comprises the cyclization of the compound of Formula VIIa to form the novel tetracyclic compounds of Formula VIII, as is illustrated by the following equation:

wherein R R R R R R and Z are as previously defined.

This dehydration is conducted in known manner, as (1) by reaction of the compound of Formula VIIa with a dehydrating agent, for example, an organic acid anhydride, such as acetic anhydride, in admixture with an alkali metal salt of an organic acid, such as sodium acetate, or an organic acid halide, for example, acetyl chloride, or (2) by reaction of the compound of Formula VIIa with an acylating agent, such as acetic anhydride and an acid, such as perchloric acid or p-toluene sulfonic acid, preferably in the presence of an organic solvent, such as ethyl acetate or benzene, if desired, under heating of the reaction mixture.

Illustrative examples of the compounds of Formula VIII include androstenones such as 17,6-hydroxy-4-oxa-9fi,10a-androst-5-en-3-one, 17 3-acetoxy-4-oxa-9fi, 10a-androst-5-en-3-one, 17 B-benzoyloxy-4-oxa-9B, 10a-androst-5-en-3-one, 1713-hydroxy-17a-methyl-4-oxa-9fi,10a-androst-5-en-3- one, 17fl-hydroxy-l7u-vinyl-4-oxa-9 9,10a-androst-5-en-3- one, l7a-ethinyl-17B-hydroxy-4-oxa-9/3, 10a-androst-5-en-3- one, 4-oxa-9fl,IOa-androst-S-en-B,17-dionc, 17 fl-hydroxy- 1-methy1-4-oxa-9I3, 10a-androst-5-en-3-one, 17/3-hydroxy-1-methoxy-4-oxa-9B,10a-androst-5-en-3- one, 17fl-hydroxy-6-methylthio-4-oxa-9/3,10a-androst-5-en-3- one, 17fl-hydroxy-2-methyl-4-oxa-9 8,10a-androst-5-en-3-one, 17/3-hydroxy-6-methyl-4-oxa-9B, la-androst-5-en-3-one, 17p-hydroxy-6-methylthio-4-oxa-9/3,10a-androst-5-en-3- one, fi-acetylthio-l7 8-hydroxy-4-oxa-9fl,10a-androst-5-en-3- one, 6-chloro-l7fi-hydroXy-4-oxa-9fi,10a-androst-5-en-3-one, 17 8-hydroxy-7-methyl-4-oxa-9 8,10a-androst--en-3-one, l 1, 17,3-dihydroxy-4-oxa-9B, l0u-androst-5-en-3-one, 1l-acetyl-17fl-hydroxy-4-oxa-9fl,10u-androst-5-en-3-one,

20 17fl-hydroxy-16-methyl-4-oxa-9p,10a-androst-5-en-3- one, 16,17fl-dihydroxy-4-oxa-9fl,10a-androst-5-en-3-one, 4-oxa-9fi,10a-androst-5-en-3-one, l7 8-hydroxy-l7a-acetic acid lactone,

and pregnenones such as 4-oxa-9B,10a-pregn-5-ene-3 ,20-dione, 2l-hydroxy-4-oxa-9fi,10x-pregn-5-ene-3 ,20-dione, 2 l -chloro-4-oxa-9fl, l 0m-pregn-5-ene-3 ,20-dione, 17a-methyl-4-oxa-9fl,10a-pregn-5-ene-3,20-dione, l7a-hydroxy-4-oxa-9 3, 1 0a-pregn-5-ene-3 ,20-dione, l7a-chloro-4-oxa-9 8,10a-pregn-5-ene-3 ,20-dione, 1-methyl-4-oXa-9fl,10a-pregn-5-ene-3 ,20-dione, 2-methyl-4-oxa-9i3,10a-pregn-5-ene-3 ,20-dione, 6-methyl-4oxa-9fi, l 0a-pregn-5-ene-3 ,20-dione, 7-methyl-4-oxa-9fi, 1 0a-pregn-5-ene-3 ,ZO-dione,

1 1-methyl-4-oxa-9p,10a-pregn-S-ene-B,ZO-dione, 16-methyl-4-oxa-9fi, l 0a-pregn-5-ene-3 ,20-dione, 16-hydroxy-4-oxa-9 3,10a-pregn-5-ene-3,ZO-dione, l6-methoxy-4-oxa-9 8, l0a-pregn-5-ene-3 ,20-dione,

and the like.

The final sequence of steps in the process of this invention comprises the aldolization of the compound of Formula VIII, followed by rearrangement and dehydration of the resulting compound of Formula IX to form a steriod of Formula I.

, The aldolization is effected by reaction of the compound of Formula VIII with a compound having the formulae R CH Li or R CH MgX wherein R is as previously defined and X is halogen, especially chlorine or bromine. Illustrative compounds include methyl lithium, ethyl lithium, benzyl lithium, methyl magnesium bromide, ethyl magnesium bromide, benzyl magnesium bromide, and the like. It is known in the normal steroid series that a Grignard reagent, for example, methyl magnesium bromide or benzyl magnesium bromide (see, for examle, the preparation of the compounds of Formula IVf above) will react with an enol lactone to form an intermediate which, on treatment with an acid or base, rearranges to form an enone. It is also known that in the l0-epi-methyl-A series the Grignard reaction proceeds with difiiculty giving little, generally less than 10 percent, and frequently no enone. It is also reported that for the 10-epi-methyl- M -series, substitution of methyl lithium for methyl magnesium bromide results in reduced yields. Unexpectedly and surprisingly, alkyl lithium compounds are superior to Grignard reagents for reaction with members of the class of compounds represented by Formula VIII, atfording considerably higher yields of the desired aldol. Accordingly, the alkyl lithium compounds of the formula R CH Li are preferred.

The novel products of the aldolization are represented by the formula:

CH: Rll vw lwvRll H on,

R H H 0 l R 5, PAGE, 0H (IX) wherein R R R R R R and Z are as previously defined.

Illustrative examples of these aldols include androstanes such as 35,l7B-dihydroxy-4,5-seco-3,6fl-cyclo-9B,10a-androstan- 5-one,

17/8-acetoxy-3-hydroxy-4,5-seco-3,613-cyclo-95,10a-

androstan-S-one,

l71S-benzoyloxy-3g-hydroxy-4,5-seco-3 ,6p-cyclo-9B, 10a.-

androstan-S-one,

3 E, 17fl-dihydroxy-17a-methyl-4,5-seco-3,6B-cyclo-9;9,10a-

androstan-S-one,

3.5,17 8-dihydroxy-17u-vinyl-4,5-seco-3,6-cyclo-913,10a-

androstan-S-one,

3.-hydroxy-4,5-seco-3,6fi-cyclo-9fl, 10a-androstan-5, l7-

dione,

35,17fi-dihydroxy-1-methyl-4,5-seco-3,65-cyclo-9fi,10a-

androstan-S-one,

3g,l7p-dihydroxy-1-methoxy-4,5-seco-3,6,8-cyclo-9;3,10a-

androstan-S-one,

3g,17fl-dihydroxy-1-methylthio-4,5-seco-3,6B-cyclo- 9B, IOa-androstan-S-one,

3E, l7/3-dihydroxy-2-methyl 4,5-seco-3, 6fl-cyclo-9 13, 10aandrostan-S-one,

3.5, 17 ,8-dihydroxy-6a-methyl-4,5 -seco-3,6 3-cyclo-9 5, 10-

androstan-S-one,

6a-acetylthio-3g, l 7fl-dihydroxy-4,5-seco-3,6,B-cyclo- 9B,10u-androstan-5-one,

60t-Ch10l'O-3 .5, 17(3-dihydroxy-4,5-seco-3,618-cyclo-9p, 10aandrostan-S-One,

3g,17/3-dihydroxy-7-methyl-4,5-seco-3,6,3-cyclo-9;3,10a-

androstan-S-one,

35,1l,17fl-trihydroxy-4,5-seco-3,6,6-cyclo-9,B,10ozandrostan--one,

1 l-acetoxy-S .E, l7fi-dihydroxy-4,5 -seco-3,6/3-cyclo-9fl,10a-

androstan-S-one,

35,17B-dihydroxy-l6-methyl-4,5-seco-3,6B-cyclo-9fi,10a-

androstan-S-one,

3 5, 16, 17 B-trihydroxy-4,5 -seco-3, 6 B-cyclo-9 3, oz-

androstan-S-one,

35-hydroxy-4,5-seco,6fl-cyclo-9p,10a-androstan-5-one 17fl-hydroxy-17a-acetic acid lactone,

3.5,17B-dihydroxy-4-methyl-4,5-seco-3,6fl-cyclo-9B,10a-

androstan-S-one,

3g, 17B-dihydroxy-4-ethyl-4,5-seco-3,6p-cyclo-9fi,10a-

androstan-S-one,

35,17fi-dihydroxy-4-phenyl-4,5-seco-3,6/3-cyclo-9p,10a-

androstan-S-one,

and pregnanes such as 3.E-hydroxy-4,5-seco-3,6B-cyclo- 9B, 10u-pregnane-5,20-dione,

3,5,21-dihydroxy-4,5-seco-3,6fi-cyclo-9fi,IOrx-pregnane- 5,20-dione,

21-chloro-3-hydroxy-4,5-seco-3,6p-cyclo-9p,10a-

pregnane-5,20-dione,

35-hydroxy-17wmethyl-4,5-seco-3,6,8cyclo-9p,10a-

pregnane-5,20-dione,

3 g, 17 u-dihydroxy-4, 5 -seco-3,6 fl-cyclo-9 18, IOa-pregnane- 5,20-dione,

17a-chloro-3-hydroxy-4,5-seco-3,6,8-cyclo-9;8,10a-

pregnane-5,20-dione,

3g-hydroxy-1-methyl-4,5-seco-3,6[3-cyclo-9fl, 10apregnane-5,20-dione,

3.5-hydroxy-2-methyl-4,5-seco-3,6,B-cyclo-9p,10a-

pregnane-5,20-dione,

3 g-hydroxy-Gu-methyl-4,5-seco3, 6p-cyclo-9 19, 10apregnane-5,20-dione,

3g-hydroxy-7-methyl-4,5-seco-3,6,8-cyclo-9p,10a-

pregnane-5,20-dione,

35,1 l-hydroxy-4,5-seco-3,6fi-cyclo-95, wot-pregnanc- 5,20-dione,

3g-hydroxy-16-methoxy-4,5-seco-3,6fl-cyclo-9}9,10o:-

pregnane-5,20-dione,

3.E-hydroxy-4-methyl-4,5-seco-3,6p-cyclo-9B,10a-

pregnane-5,20-dione,

and the like.

The reaction temperature is not narrowly critical, and can vary from 0 C. to about 100 C., with temperatures 22 of from about 20 C. to about 40 C. being preferred. The reaction is preferably effected in the presence of a suitable solvent, such as ether, benzene, tetrahydrofuran, dioxane, or mixtures thereof.

The final step of rearrangement and dehydration of the aldols of Formula IX to produce the retrosteroids of Formula I is effected by treating the aldol of Formula IX with acid or base in known manner. Preferred are organic or inorganic acids such as hydrochloric or sulfuric acid or para-toluenesulfonic acid, and organic or inorganic bases such as sodium or potassium hydroxide or potassium tertiary butoxide. This reaction is preferably effected in a suitable solvent such as water, lower alkanols, for example, ethanol, propanol, or tertiary butanol, benzene, dioxane, or t-etrahydrofuran. Other reaction conditions are not narrowly critical, although temperatures above about C. are to be avoided with basic treatment to avoid the reverse Michael reaction.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g., capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative. In the examples, the assigned structures of the products were confirmed by infrared, ultraviolet, and/or nuclear magnetic resonance spectra, and/or elemental analysis.

EXAMPLE 1 l75-hydroxy-5-oxo-3,5-seco-A-nor-9B,10a-androstan-3- nitrile from 17,3-hydroxy-9fi,l0/3-desA-androstan-5-one To a solution of 5.9 g. of 17fi-hydroxy-9B,10B-desA- androstan-S-one and 3.5 ml. of freshly distilled acrylonitrile in 250 ml. of anhydrous dioxane, which was stirred at room temperature, was added 21 ml. of a 40 percent benzyltrimethyl-ammonium hydroxide solution in methanol. The reaction mixture so-obtained was stirred at room temperature for seven days, then cooled to 13-15 and acidified by addition of glacial acetic acid. After evaporation to dryness in vacuo, the residue was dissolved in 1000 ml. of chloroform. The last solution was extracted several times with 40-50 ml. portions of saturated aqueous sodium chloride solution, and after drying over anhydrous sodium sulfate, it was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column with a petroleum ether-ether system to give l7fi-hydroxy 5 oxo-3,S-seco-A-nor-9{3,10a-androstane-S-nitrile as an oil at room temperature.

EXAMPLE 2 17 fi -hydroxy-5-oxo-3,5 -seco-A-nor- 9,8,l0a-androstane-3-nitrile A solution of potassium tertiary butoxide was prepared by dissolving 985 mg. of potassium in 100 ml. of anhydrous tertiary butanol, and after cooling to room temperature, it was combined with a solution of 5.9 of 17a hydroxy-9fl,l0l3-desA-androstan-5-one in ml. of anhydrous tertiary butanol. After stirring for 30 minutes, a solution of 2.5 ml. of freshly distilled acrylonitrile in 25 ml. of anhydrous tertiary butanol was added, and the reaction mixture was left for 22 hours at room temperature. It was then acidified with 1.6 ml. of glacial acetic acid, and evaporated to dryness in vacuo. The residue was dissolved in 1 l. of chloroform, and the soobtained solution was washed twice with 50 ml. of saturated sodium chloride solution, and, after drying over anhydrous magnesium sulfate, evaporated to dryness. The residue was chromatographed on a silica gel column with a petroleum ether-ether system to give 17,8-hydroxy-5-oxo- 3,5-seco A nor-913,10a-androstane-3-nitrile, which was identical to the compound prepared in Example 1.

23 EXAMPLE 3 17 8-acetoxy-5-oxo-A-nor 3,5 seco-9fi,10u-androstan-3- oic acid from 17,B-hydIoxy--oxo-A-nor-3,5-seco-9fl, a-andr0stane-3-nitrile A mixture of 3.6 g. of 17fl-hydroxy-5-oxo-A-nor-3,5- seco-9/3,10a-androstane-3-nitrile in 160 ml. of 10 percent aqueous potassium hydroxide solution was refluxed for six hours. After cooling, it was diluted with 200 ml. of water and extracted with 200 ml. of ether. The ether extract was washed with 50 ml. of 2 N sodium carbonate solution. The carbonate layer was combined with the alkaline reaction mixture, and after cooling in an ice bath, acidified with concentrated hydrochloric acid. The resulting suspension was extracted with four 200-ml. portions of methylene chloride, and the combined extracts washed with 150 ml. of water, dried over anhydrous magnesium sulfate, and evaporated. The crude acid was dissolved in ml. of pyridine and after the addition of 10 ml. of acetic anhydride left overnight at room temperature. It was then evaporated to dryness, and the residue chromatographed on a silica gel column with a methylene chloride-ether system to give crystalline-17 3-acetoxy-5- oxo-A-nor-3,5-seco-9B,10x-androstan-3-oic acid. After recrystallization from ethanol it melted at l34134.5.

EXAMPLE 4 17,3-hydroxy-5-oxo A nor-3,5-seco-9fl,IOa-androstan-B- oic acid from l7B-hydroxy-5-oxo-A-nor-3,5-seco-9fl, 10a-androstane-3-nitrile A mixture of 1.35 g. of 17 3-hydroxy-5-oxo-A-nor-3,5- seco-9,8,10u-androstane-3-nitrile and 60 ml. of 10 percent potassium hydroxide solution was refluxed for 5.5 hours in a nitrogen atmosphere. It was then diluted with water to 500 ml. and extracted several times with ether. The combined ether extracts were washed with 250 ml. of 2 N sodium carbonate solution. The aqueous alkaline layers were combined, and after cooling in an ice bath, acidified with concentrated hydrochloric acid. The suspension so-obtained was extracted several times with methylene chloride. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methylene chloride and isopropyl ether to give 17,3-hydroxy-S-oxo-A-nor-3,5-seco-9fl,10a-androstan-3-oic acid, M.P. 129-132". An analytical sample was prepared by recrystallizations first from methylene chloride-petroleum ether and then from acetone-petroleum ether, M.P. 132- 134.

EXAMPLE 5 17B-hydroxy-5-oxo A nor-3,5-seco-9B,10u-androstan-3- oic acid from 17/3-acetoxy-5-oxo-A-nor-3,5-seco-9 S, 10a-androstan-3-oic acid A solution of 10 g. of 17fl-acetoxy-5-oxo-A-nor-3,5- seco-9 3,10a-androstan-3-oic acid and 6 g. of potassium hydroxide in 150 ml. of 75 percent aqueous methanol was refluxed for two hours, and then evaporated to dryness in vacuo. The residue was dissolved in 100 ml. of water, and after cooling to 0, acidified with 20 percent hydrochloric acid. The resulting suspension was extracted with methylene chloride, the extract was washed with water, dried and evaporated. The residue was crystallized from ethylacetate to yield 17,8-hydroxy-5-oxo-A-nor-3,5- seco-9p,10u-androstan-3-oic acid, M.P. 132.5133.

EXAMPLE 6 17B acetoxy-4-oxa-9fi,10a-androst-5-en-3-one from 175- acetoxy-S-oxo A nor-3,5-seco-9fi,10a-androstan-3-oic acid A mixture of 3 g. of 17,3-acetoxy-5-oxo-A-nor-3,S-seco- 9 8,l0a-androstan-3-oic acid, 30 ml. of acetic anhydride and 400 mg. of anhydrous sodium acetate was refluxed for 2 hours, and then evaporated in vacuo. The residue 24 was treated with water and extracted in ether. The ether extract was washed with water, dried and evaporated. The residue was crystallized from isopropyl ether to give 17fi-acetoxy-4-oxa-9fi,10a-androst-5-en-3-one, M.P. 92.5- 93.

EXAMPLE 7 17B acetoxy-4-oxa-913,10a-androst-5-en-3-one from 17 13- acetoxy-S-oxo A nor-3,5-seco-9 8,10a-androstan-3-oic acid The experiment of Example 6 was repeated, except that l7B-hydroxy-5-oxo A nor-3,5-seco-9fi,l0a-androstan-3- oic acid was substituted for 17B-acetoxy-5-oxo-A-nor-3,5- seco-9f3,10u-androstan-3-oic acid.

EXAMPLE 8 -acetoxy 3g hydroxy 4,5-seco 3,6/8-cyclo-9fl,l0aandrostan-S-one and 3g,17/3-dihydroxy-4,5-seco-3,6B- cycle-9,3,10a-androstan-5-one from 17fl-acetoxy-4-oxa- 9 8,10a-androst-5-en-3-one To a solution of 1336 mg. of 17 8-acetoxy-4-oxa-9p, 10ot-androst-5-en-3-one in 320 ml. of anhydrous benzene was added 3 mole equivalents of methyl lithium in ether solution, and the reaction mixture was left for 70 minutes at room temperature. After dilution with 600 ml. of benzene it was washed with 50 ml. of 1 N sodium thiosulfate solution and two SO-ml. portions of 15 percent sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with a petroleum ether-ether system. Oily 17B-acetoxy-3.-hydroxy-4,5-seco-3,6,6-cyclo- 9fi,10a-androstan-5-one was first eluted from the column, and then oily 3.5,17fl-dihydroxy-4,5-seco-3,6 3-cyclo-9fi, 10a-androstan-5-one.

EXAMPLE 9 17;3-acetoxy-9B,10a-androst-4-en-3-one and 17/3-hydroxy- 9/8,10u-androst-4-en-3-one from 17B-acetoxy 35 hydroxy-4,5-seco-3,6fl-cyclo-9B,l0a-androstan-5-one and 3E,17/8-dihydroxy 4,5 seco-3,6;8-cyclo-9/3,10a-androstan-S-one The solution of 2359 mg. of the crude mixture of 17B-acetoxy 3E hydroxy 4,5-seco-3,6B-cyclo-9;8,10aandrostan-S-one and 35,17,8-dihydroxy 4,5 sew-3,65- cyclo-9 3,10a-androstan-5-one, produced as described in Example 8, and 288 mg. of para-toluene sulfonic acid monohydrate in 400 ml. of anhydrous benzene was refluxed for 2 hours with azeotropic removal of the water formed in the reaction. After cooling the reaction mixture was diluted with 200 ml. of ether, then washed with 40 ml. of ice cold 7 percent aqueous sodium bicarbonate solution, 40 ml. of ice cold 1 N sodium hydroxide solution and three 40-ml. portions of ice cold water. The water layers were washed with two 400-ml. portions of ether. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue, an oil weighing 1957 mg., was chromatographed on a 60 g. silica gel (0.05-0.2 mm.) column with a petroleum ether-ether eluting system. From the column was first eluted 17/3-acetoxy-9B,10a-androst- 4-en-3-one, which after several recrystallizations from isopropyl ether-petroleum ether, melted at 113.5-114.5. Later, 17;.9-hydroxy 9,3,100: androst-4-en-3-one was eluted from the column, and, after several recrystallizations from isopropyl ether-petroleum ether mixture, it melted at 156-1565.

EXAMPLE 10 17fl-benzoyloxy 913,100: androst-4-en-3-one from 175- acetoxy-3g-hydroxy-4,5-seco 3,63 cyclo-9 8,10a-androstan-5-one and 35,17/3-dihydroxy-4,5-seco-3,6fl-cyclo-9 3, 10u-androstan-5-one A solution of 2077 mg. of a crude mixture of 17/3- acetoxy-3.5-hydroxy-4,5-seco-3,6,8-cyclo 913,100: androstan-S-one and 3g,17fl-dihydroxy-4,5-seco-3,6/3-cyclo-9, lOu-androstan-5-one obtained as described in Example 8 and one mole equivalent of potassiumtertiary butoxide in 68 ml. of anhydrous tertiary butanol was stirred at room temperature for 10 minutes, then acidified with 1.5 ml. of acetic acid and evaporated. The residue was taken in 500 ml. of ether and washed with two 50ml. portions of 10 percent aqueous sodium carbonate solution, and two 50-ml. portions of percent aqueous sodium chloride solution, then dried over anhydrous sodium sulfate and evaporated. The residue was partially purified on a silica gel column, and 780 mg. of a fraction with ultraviolet absorption of 6 11,500 was dissolved in 2.7 ml. of pyridine, and to this solution was added in portions a solution of 500 mg. of benzoyl chloride in 0.8 ml. of benzene. The reaction mixture was stirred at room temperature for 18 hours, then filtered, and the filtrate diluted with 400 ml. of ether. The ether solution was washed with 100 ml. of 5 percent sodium carbonate solution, 100 ml. of 18 percent hydrochloric acid, 100 ml. of 5 percent sodium carbonate solution and three 100-ml. portions of water, then dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on an aluminum oxide column to give crystalline 17B- benzoyloxy-9p,10u-androst-4-en-3-one, which after recrystallization from a methylene chloride-hexane mixture, melted at 155156.

EXAMPLE 11 17B-benzoyloxy-9p,10a-androst-4-en-3-one from 17fl-hydroxy-9fi,IOmandrost-4-en-3-One To a solution of 2190 mg. of l7fl-hydroxy-9fl,'l0aandrost-4-en-3-one in 7.5 ml. of pyridine was added in portions a solution of 1260 mg. of benzoyl chloride in 2.25 ml. of benzene. The reaction mixture was stirred for 18 hours at room temperature, then filtered and the filtrate diluted with 500 ml. of ether. The ethereal solution was washed with 100 ml. of 5 percent sodium carbonate solution, 100 ml. of 18 percent hydrochloric acid, 100 ml. of 5 percent sodium carbonate solution and three 100-ml. portions of water, then dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on an aluminum oxide column with a henzene-petroleum ether system to give 17fi-benzoyloxy- 9 3,10a-androst-4-en-3-one, which after three recrystallizations from a methylene chloride-hexane mixture melted at 155-156".

EXAMPLE 12 5,17-dioxo-A-nor-3,5-seco 93,100; androstan-3-oic acid from 17B-hydroxy-5-oxo A-nor-3,5-seco-9p,lOut-androstan-3-oic acid To a stirred solution of 3 g. of l7B-hydroxy-5-oxo-A- nor-3,5-seco-9p,10a-androstan-3-oic acid in 80 ml. of acetone at 0, was added 4 ml. of Jones reagent (0.016 mole of chromium trioxide equivalent), and the reaction mixture was stirred for 10 minutes. After addition of 10 ml. of methanol, the reaction mixture was evaporated in vacuo. After the addition of 50 ml. of water to the residue, the mixture was extracted with ether. The ethereal extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The product, 5,17-dioxo-A-nor-3,5-seco 95,10a androstan-3-oic acid, was an oil, which crystallized upon the addition of petroleum ether. After recrystallization from ethylacetate, it melted at 128-1285".

EXAMPLE 13 4-oxa-9B,10a-androst-5-ene-3,17-dione from 5,17-dioxo- A-nor-3,5-seco-9 3,10a-androstan-3-oic acid A mixture of 2.2 g. of 5,17-dioxo-A-nor-3,5-seco-9 8, 10a-androstan-3-oic acid, 20 ml. of acetic anhydride and 400 mg. of anhydrous sodium acetate was refluxed for 2 hours, and then evaporated to dryness in vacuo. To the residue was added water, and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and evaporated, to give crystalline 4-oxa-9fi, 10u-androst-5-ene-3,17-dione, which after recrystallization from isopropyl ether melted at 116.5-5-117.

Employing procedures similar to those described in Examples 8 and 9, the 4-oxa-9 3,IOa-androst-S-ene-S,17-dione is converted first to 35 hydroxy-17fl-oxo-4,5-seco-3,6 3- cycle-95,10a-androstan-5-0ne and then to 9/3,10a-androst- 4-ene-3,17-dione.

EXAMPLE 14 17B hydroxy 17a-methyl-5-oxo-3,5-seco-A-nor-9fl,10a-

androstane 3-nitrile from 17 B-hydroxy-17a-methyl-9p, IOB-desA-androstan-S-one To a solution of 2 g. of Nil-hydroxy-17u-methyl-9B, IOB-desA-androstan-S-one in ml. of anhydrous freshly distilled tertiary butanol was added a solution of 8 millimoles of potassium tertiary butoxide in 80 ml. of anhydrous tertiary butanol, and, after stirring for 30 minutes, 1.06 ml. (16.2 millimoles) of freshly distilled acrylonitrile was added. The reaction mixture so-obtained was stirred at room temperature for an additional five hours, and then acidified with 0.5 ml. of glacial acetic acid, and evaporated in vacuo. The residue was taken in 1.5 l. of chloroform, and the resulting solution washed with two 5 O-ml. portions of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The crude product so-obtained was chromatographed on a silica gel column with a petroleum ether-ether system to give 17B-hydroxy-l7a-methyl-5-oxo- 3,5-seco-A-nor-9 3,l0u-androstane-3-nitrile, which was distilled in high vacuum and crystallized from an acetoneether-hexane mixture, M.P. 94.5-95.5. The 17B-hydroxy- 17a-methyl-5-oxo-3,5-seco-A-nor-9B,10u-androstane-3- nitrile is then converted to the corresponding acid in the manner described in Example 4.

EXAMPLE 15 17,9 acetoxy 17a-methyl-4-oxa-9p,10a-androst-5-en-3- one from 17,53 hydroxy 17ot-methyl-5-oxo-A-nor-3,5- seco-9fi,10a-androstan-3-oic acid A mixture of 3 g. of 17fl-hydroxy-17m-methyl-5-oxo-A- nor-3,5-seco-9 3,10u-androstan-3-oic acid, 30 ml. of acetic anhydride and 0.5 g. of anhydrous sodium acetate was refluxed for 2 hours, and then evaporated. To the residue water was added and the mixture was extracted with methylene chloride. The organic extract was washed with water, dried, and evaporated, to give crystalline 17fl-acetoxy- 17a-methyl-4-oxa-9p,l0a-androst-5-ene-3- one, which after recrystallization from ethylacetate melted at 1715-1745 EXAMPLE 16 acetoxy-3E-hydroxy-17a-methyl-4,5-seco-3,6B-cyclo- 9fl,l0u-androstan-5-one from 17-acetoxy-17a-methyl-4- oxa-9fl,l0ot-androst-5-en-3-one To a stirred solution of 3.12 g. of 17/3-acetoxy-17umethyl-4-oxa-9p,10a-androst-5-en-3-one in 750 ml. of anhydrous benzene were added 3 mole equivalents of methyl lithium in ether solution, and the reaction mixture was left for 70 minutes at room tempeature. After dilution with 600 ml. of benzene, it was washed with 50 ml. of 1 N sodium triosulfate solution, and two 50-ml. portions of 15 percent sodium chloride solution, then dried over anhydrous magnesium sulfate, and evaporated. The residue was chromatographed on a silica gel column with a petorelum ether-ether system to give oily 17fi-acetoxy-3- hydroxy 17o: methyl-4,5-seco-3,6p-cyclo-9 3,10a-androstan-S-one.

EXAMPLE 17 17B acetoxy l7a-methyl-9fl,10a-androst-4-en3-one and 17 fi-hydroxy-l 7a-methyl-9fi, 10w androst-4-en-3 -one The mixture, 2832 mg., obtained as described in Example 16, and containing in part l7fl-acetoxy-3E-hydroxy- 170; methyl-4,5-seco-3,6B-cyclo-9fi,IOa-androstan-S-one, was dissolved in 300 ml. of benzene. To this solution was added 2 mole equivalents of potassium tertiary butoxide dissolved in tertiary butanol and after 150 minutes the reaction mixture was evaporated to dryness. The residual red oil was dissolved in 800 ml. of methylene chloride, and the solution washed with two 400-ml. portions of water. The combined aqueous portions were re-extracted twice with 800 ml. of methylene chloride. The combined methylene chloride layers were dried over anhydrous sodium sulfate, and evaporated to dryness, to give 2396 mg. of a red oily residue. This residue was chromatographed on a 50 g. silica gel (0.050.2 mm.) column with a pe troleum ether-ether eluting system. First from the column was eluted 175 acetoxy-l7a-methyl-9fi,10a-androst-4-en- 5-one, which melted at 143-l44 after recrystallization from a mixture of methylene chloride-isopropyl etherpetroleum ether. Later from the column was eluted 17 3- hydroxy 17a methyl-95,la-androst-4-en-3-one, which after several recrystallizations from isopropyl ether-petroleum ether mixture melted at 129-1295".

EXAMPLE 18 20-oxo-9p,17,8-pregn-4-en3-one from 20-ethylenedioxy- 9p,1OB-desA-17fi-pregnan-5-one Employing techniques as described above, ZO-ethylenedioxy 95,103 desA l7B-pregnan one, produced by ketalization of 20 oxo-9p,IOa-desA-pregnan-S-One with ethyleneglycol, is reacted with acrylonitrile in the presenc of benzyltrimethylammonium hydroxide to produce 20 ethylenedioxy-3,5-seco-A-nor-9p,10,17p-pregnane-3- nitrile, which on refluxing with potassium hydroxide and acidification with hydrochloric acid yields the corresponding carboxylic acid. The 20-ethylenedioxy-5-oxo-A-nor-3, 5 seco-9,9,10a,17fl-pregnan-3-oic acid is refluxed with acetic anhydride and sodium acetate, and the resulting 20' ethylenedioxy-4-oxa-9/3,10a,l7fl-pregn-5-en-3-one reacted with methyl ltihium to produce 20-ethylenedioxy-3g-hydroxy 4,5 seco 3,613 cycle-9,3,l0a,l7B-pregn-5-one, which, on refluxing with p-toluenesulfonic acid and benzene with azeotropic removal of water, yielded ZO-ethylenedioxy-9p,l0u,17 8-pregn-4-en-3-one. Treatment of this product with acetic acid yields 9fi,l0a,l7fl pregn-4-en-3, 20-dione.

What is claimed is:

1. A 9,8,10a-retrosteroid of the formula:

(VIII) 28 R is a member selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, and, when the 17fl-substituent is Z is a member selected from the group consisting of carbonyl, (l7fl-hydroxy-l7a-lower alkanoic acid lactone), and

R is a member selected from the group consisting of hydroxy, lower alkanoyloxy, and

YCHgE- Y is a member selected from the group consisting of hydrogen, halo, and hydroxy; and

R when R is hydroxy and lower alkanoyloxy, is

a. member selected from the group consisting of hydrogen and lower alkyl and, when R is 0 YCHgHJ- is a member selected from the group consisting of hydrogen, alkyl, hydroxy, lower alkanoyloxy, and halo.

2. A compound as claimed in claim 1 having the formula:

wherein R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, and halo;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, and halo;

R is a member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy;

A is a member selected from the group consisting of carbonyl, (17}3-hydroxy-17a-lower alkanoic acid lactone), and

R is a member selected from the group consisting of hydrogen and lower alkanoyl;

R is a member selected from the group consisting of hydrogen and lower alkyl; and

R is a member selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, and lower alkanoyloxy.

3. A compound as claimed in claim 2 having the formula:

wherein n is an integer having a value of from to 6 and x is an integer selected from the group consisting of those having a value represented by 2n+1, 211-1, and 211-3 and lower alkanoic esters thereof. 4. A compound as claimed in claim 1 having the formula:

wherein p R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and lower alkylthio;

R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio, and halo;

wherein n is an integer having a value of from 0 to 6 and y is an integer having a value of from 0 to 1.

References Cited UNITED STATES PATENTS 2,897,202 7/1959 Wildi 260-343.2 X 3,329,688 7/1967 Edwards et al 260-343.2

JOHN M. FORD, Primary Examiner US. Cl. X.R.

260-3973, 397.1, 397.4, 586 R, 343, 343.5, 343.6, 343.9, 468 F, 514 R, 464, 488 B UNITED STATES PATENT OFFICE CERTIFICATE 0F CORRECTION Patent 3,766,213 Dated October 16, 1973 Inventofls) Andor Furst, Wolfgang Koch & Milan Radoje Uskokovic It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 28, line 65,

should be Signed and sealed this 29th day of October 1974.,

(SEAL) Attest:

C. MARSHALL DANN McCOY M. GIBSON JRu Attesting Officer Commissioner of Patents FORM (10459) uscoMM-Dc eoa1eq=es U.S. GOVERNMENT PRINTING OFFICE: I965 366"3 fl. 

